In vitro testing: The quiet revolution
In 1985 in vitro tests accounted for 1% of all R&D testing carried out by CROs and pharma companies. In 2013 it had risen to over 20%. The sophistication of in vitro techniques has improved dramatically over a range of fields. Yet it is a success story that in some ways has gone unreported. What benefits can in vitro testing deliver? And how big a role might it play in the future? ISAB’s in vitro manager Maria Malmlöf has the facts.
On 24 November 2015 a quiet revolution took place. UK generics company Circassia announced it had received European approval for its generic fluticasone propionate pMDI (pressurised metered dose inhaler) – following “in vitro demonstration of equivalence only, without the need for clinical data.”
The in vitro-only approval follows decades of technological progress in in vitro testing:
- In 1985 in vitro tests accounted for 1% of all R&D tests carried out by CROs (Contract Research Organizations), and less than that for pharma companies.
- In 2013 in vitro accounted for 15% of all R&D tests carried out by CROs, and more than 20% of R&D tests carried out by pharma companies.
(Development and use of in vitro alternatives to animal testing by the pharmaceutical industry 1980–2013. Jen-Yin Goh,a Richard J. Weaver,b Libby Dixon,a Nicola J. Platta and Ruth A. Roberts)
Regulators favour in vitro testing
In the EU and US regulators have noted this progress. In 2012 the European Medicines Agency (EMA) revised its concept paper on the replacement of animal studies with in vitro tests to “more clearly define the process for regulatory acceptance of alternatives”, recognizing “the increased use of in vitro methods” and “the need for formal validation studies on some occasions, and proof of scientific validity on others.” (Revised Concept paper on the need for revision of the position on the replacement of animal studies by in vitro models (CPMP/SWP/728/95)
“Regulatory bodies in the EU and US are both becoming increasingly favourable towards in vitro research,” says ISAB in vitro manager Maria Malmlöf. She points out that regulatory change around in vitro testing has been slower in inhalation than other fields, given the notorious complexity of delivering drugs to the lung. Recent regulatory recommendations on, for example, the testing of biosimilars (low-cost generic copies of biologic drugs) actively encourage developers to use in vitro tests:
“EU and US guidelines recommend a step-wise approach to testing including in vitro tests. In vitro studies should be conducted first, and a decision then made as to the extent of what, if any, in vivo work will be required”. (Pharmaceutical toxicology: Designing studies to reduce animal use, while maximizing human translation, 2013) Biosimilars earned 4.8 BUSD in sales in Europe in 2015. When launched in the US sales are predicted to go even higher (Forbes.)
“Regulators value in vitro testing as a way of replacing, reducing and refining the use of animals,” says Malmlöf. “And as a way of making drug development faster and more efficient. In vitro testing early on saves drug developers time and money. It is a crucial strategic tool for them. It gives them an early warning signal against clinical failure, and helps them rank drug candidates – weeding out poor performers early on, and potentially saving millions on reformulating midway through trials.”
In the complex, multidisciplinary area of the lung ISAB’s in vitro solutions have been described as “leading” by in vitro researchers at King’s College London and Karolinska Institutet.
DissolvIt: Simulated lung module
ISAB’s DissolvIt module enables in vitro simulation of respirable particles in the lung epithelium. In DissolvIt dry powder particles are deposited on a glass surface by PreciseInhale. The particles are then brought into contact with an artificial lung surface medium and the dissolution is studied, both from the “luminal” side through optical microscopy and from the “vascular” side by chemical analysis of a flow past perfusion medium. The system consists of a flow past cell, a precision?controlled peristaltic pump and an inverted microscope with a high resolution camera. The flow past cell is perfused in single?pass mode after which the perfusate is collected in a fraction collector. The entire system is thermostatted to 37° C.
XPOSEALI : 3-D in vitro cell exposure
XposeALI, ISAB’s 3D cell exposure module, combines aerosol capability with 3D cell models cultured in an Air Liquid Interface (ALI.) The exposure system is thermostatted to 37°C and the cells are in contact with media from below during the entire exposure. After aerosol exposure, the cells are brought back to the incubator for an appropriate time period. In this way the aerosol exposure induced cellular effects can be studied by analyzing the cells.